This proposal describes a 5 year training program for the development of an academic career in Dermatology. The principal investigator has completed over 90% of his structured residency training in Dermatology at UCLA, and is currently expanding his scientific skills through a program committed to promoting careers in academic medicine by integrating dermatology residency training with a two-year protected postdoctoral research fellowship. This program will promote the command of innate immunology, as applied to the dermatologic infectious disease, leprosy. Dr. Robert Modlin will mentor the principal investigator's scientific development and is a recognized leader in the field of leprosy and human immunology, with current ongoing studies in his laboratory involving the mechanisms of host defense and innate immunity in skin, both of which are relevant to this proposal. The principal investigator's long-term career goal is to be an independent investigator in academic dermatology with his own laboratory. The research proposal is based upon the hypothesis that the activation of distinct DNA receptors in skin immune cells confers distinct cytokine responses, thereby determining the outcome of the immune response. The specific aims include: 1) determine the mechanisms by which recognition of DNA ligands, including those of the Mycobacterium leprae short tandem repeats, contribute to host defense in skin by innate immune cells, 2) elucidate the mechanisms of DNA recognition that determine functional responses in macrophages and dendritic cells, 3) determine the role of the specific DNA recognition pathways in leprosy. It is anticipated that the proposed studies will provide novel insight into mechanisms of innate immunity in human skin, providing new therapeutic strategies to intervene in a range of skin diseases, including those of infectious, immunologic and neoplastic etiology. CANDIDATE AND ENVIRONMENT: The principal investigator is a post-graduate researcher with doctoral training in both dermatology and immunology. The breadth of his training allowed for the conception and synthesis of this proposal, which spans the fields of innate immunity, infectious disease, and skin biology: The candidate will be under the mentorship of Robert Modlin, a world-renowned immunologlst and dermatologist at UCLA. GOALS AND CAREER DEVELOPMENT: The immediate goal will be to explore the mechanism of host DNA recognition by innate immune cells in skin according to the induction of distinct cytokine responses. This will be accomplished using leprosy as a model, with the results having broad implications for a spectrum of skin diseases. The long term goal will be to use this experience to become an established investigator who can apply these immunologic principles to gain insight and develop novel therapies for other skin diseases. RELEVANCE: The ability of innate immune cells in skin to recognize DNA is a novel immunologic mechanism that influences the innate immune response, and can be studied using leprosy as a model. Investigations in leprosy have helped establish immunologic paradigms that direct disease treatment, including type 1 and type 2 T cell immunity and the function of Toll like receptors in microbial infection. Through the work in this proposal, we will define the mechanisms by which cells of the innate immune system in skin recognize DNA patterns, leading to the induction of distinct cytokine responses that contribute to disease pathogenesis.